小儿病毒性肺炎风寒郁肺证的代谢组学研究
发布时间：2018-07-23 14:12
【摘要】：背景:儿童社区获得性肺炎(CAP)已经逐渐成为导致全世界5岁以下儿童死亡的第一位病因。全球每年死于肺炎的患儿统计数据大约是200万,这占到全球范围内儿童死亡总数的200%。病毒感染是小儿CAP区别于成人的重要特征。其中以呼吸道合胞病毒(Respiratory Syncytia1 Virus;RSV)占首位[1],其他病毒如腺病毒(Adenovirus,ADV)、流感病毒(Inf1uenza virus,IFV)、人类偏肺病毒(Human meta-pneumoniae virus,hMPV)副流感病毒(Parainfluenza virus,PIV)等。就中医病名而言,儿童CAP可划为"肺炎喘嗽",风寒郁肺证常作为小儿病毒性肺炎起初的重要证候,如何全面地、科学地阐述这一中医证候内涵与本质,成为现代中医学需解决的迫切问题。据相应的研究显示,儿童病毒性肺炎的治疗上,缺乏完全有效、安全的理想化合药物,病毒唑(Ribavirin)是唯一被美国儿科协会(AAP)谨慎推荐的"也许能够使用"的合成核苷类抗病毒药物。相较于此,中医药在治疗小儿病毒性肺炎上显示出明显优势,且已经为大量临床和实验研究所证实。代谢组学(Metabolomics)作为系统生物学的重要组成部分,是聚焦于生物体内源性代谢物性质、数量、种类及其整体变化规律的一门崭新学科[2]。代谢组学可以有效避免既往蛋白组学或基因组学单独采用一种或几种指标,或者一条或几条基因阻断后的通路表达就预测或推断生理状态或病理情况的"真实世界",同时却可以及时地、有效地、客观灵敏地映射生物体受外界扰动后机体内基因、蛋白、细胞或组织的"生化表型",以整体衡量取代单一检测,这十分契合中医基础理论的"整体观、恒动观",是一种以"航拍视觉"替换单一"丛林搜索"的角度。基于此种宏观认识,本课题采用代谢组学方法,结合患儿生命体征,血、尿常规,肝、肾功能等生化检测,整体出发探讨病毒性肺炎风寒郁肺证(WC)所导致的代谢差异的意义,试图从小分子代谢角度解释小儿病毒性肺炎风寒郁肺证的证候内涵。目的：整体角度探讨小儿病毒性肺炎风寒郁肺证患儿的血清和尿液的内源性差异代谢特征,阐释小儿病毒性肺炎风寒郁肺证的差异代谢证候实质。方法:小儿病毒性肺炎风寒郁肺证组学技术的临床实验:挑选可以纳入中西医诊断标准的病毒性肺炎属于风寒郁肺证型的患儿30例,设为风寒组(WC),同时设立体检时的正常健康儿童30例(NH)。分别在入院第二天收集两组儿童的血清和尿液,采用气相色谱-质谱联用仪(Gas-Chromatography-MassSpectrometry,GC-MS)同时分析获取WC组和NH组血清、尿液中的差异内源性代谢物,基于数据库成立小儿病毒性肺炎风寒郁肺证的证候相关代谢集群,通过在线分析平台XCMS Online预处理、NIST数据库和已有标准品进行验证、MetaboAnalyst确定差异性代谢物及代谢路径,解释所涉及的相关通路,揭示小儿病毒性肺炎风寒郁肺证的差异代谢特点和本质。结果:1.血清代谢组学模式识别分析结果显示,风寒郁肺证与健康儿童组间能够良好区分,众多有机酸、氨基酸、脂类等差异性代谢物及代谢通路被确定。与健康儿童相比,风寒郁肺证患儿血清中丙氨酸、天冬氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、牛磺酸、赖氨酸等多种有机酸、氨基酸上调;氨基丁酸、乙醇酸、甘油、1-棕榈酸单甘油酯、胆固醇、葡萄糖等下调。2.尿液代谢组学模式识别分析结果显示,风寒郁肺证与健康儿童组间虽有一定分离趋势,但仍存在交叉重叠,进一步建模OPLS-DA,两组完全分离,说明代谢物存在差异。尿液代谢中甘氨酸、丝氨酸、色氨酸、β-羟基丁酸、葡萄糖酸、D-半乳糖、肌苷、尿苷等物质上调;羟基乙酸、硬脂酸、棕榈酸等下调。结论:1.GC-MS代谢组学技术平台能够良好区分和初步解答小儿病毒性肺炎风寒郁肺证(WC)与正常健康儿(NH)之间的差异代谢。2.病毒性肺炎WC证患儿的血清和尿液代谢中主要以丙氨酸、甘氨酸、牛磺酸代谢、花生四烯酸、棕榈酸代谢等代谢紊乱为标志。
[Abstract]:Background: Children's community-acquired pneumonia (CAP) has gradually become the first cause of death in children under 5 years of age. The statistics of children who die of pneumonia every year around the world are about 2 million. This accounts for the 200%. virus infection of the total number of children in the world, which is an important feature of children's CAP different from adults. Respiratory Syncytia1 Virus (RSV) accounts for the first [1], other viruses such as Adenovirus (ADV), influenza virus (Inf1uenza virus, IFV), human partial lung virus (Human meta-pneumoniae) parainfluenza virus (Human meta-pneumoniae), etc. As an important symptom of viral pneumonia at the beginning of children, how to comprehensively and scientifically explain the connotation and essence of the TCM syndrome has become an urgent problem to be solved in modern Chinese medicine. According to the corresponding research, the treatment of viral pneumonia in children is lack of complete effective, safe and ideal combination drug, and Ribavirin is the only one. AAP, which is carefully recommended by the American paediatrics Association, "may be able to use" synthetic nucleoside antiviral drugs. Compared with this, traditional Chinese medicine has shown obvious advantages in the treatment of viral pneumonia in children, and has been confirmed by a large number of clinical and experimental studies. Metabolomics (Metabolomics) is an important component of system biology. A new subject, [2]. metabolomics, which is a new subject in the nature of endogenous metabolites, quantity, species, and overall changes of organisms. It can effectively avoid the previous proteomics or genomics by using one or several indicators, or the expression of one or several genes blocking the pathway to predict or infer physiological or pathological conditions. "Real world", at the same time, it can be timely, effectively and objectively and sensitively map the organism, protein, cell or tissue "biochemical phenotypes" in the body after disturbance, and replace the single detection by the whole measure. This fits the basic theory of traditional Chinese medicine, the concept of holism, the concept of constant motion, is a kind of "aerial vision" replacing a single "jungle search". On the basis of this macro understanding, this subject uses the metabonomics method, combined with the biochemical tests of children's life signs, blood, urine routine, liver and kidney function, and discusses the significance of metabolic difference caused by the WC of viral pneumonia and wind cold depression, and tries to explain the syndrome of the wind cold and depressed lung syndrome of children with viral pneumonia from an early age. Objective: To explore the endogenous differential metabolism characteristics of serum and urine in children with viral pneumonia, wind cold and depression, and to explain the essence of differential metabolic syndrome in children with viral pneumonia, wind cold and depressed lung syndrome. Methods: clinical experiment of children viral pneumonia in wind cold depression and lung syndrome: selection can be included in Chinese and Western medicine. The standard viral pneumonia belongs to 30 children with wind cold and lung syndrome type, which is set as the wind cold group (WC). At the same time, 30 cases of normal healthy children (NH) were set up at the physical examination. The serum and urine of two groups of children were collected for second days in the hospital, and the WC group was obtained by gas chromatography-mass spectrometry (Gas-Chromatography-MassSpectrometry, GC-MS) simultaneously. The difference of endogenous metabolites in the serum and urine of NH group, based on the database to establish the syndrome related metabolic clusters of children with viral pneumonia, wind cold and depression, was pretreated by the online analysis platform XCMS Online, the NIST database and the existing standard, and MetaboAnalyst to determine the differential metabolites and metabolic pathways. The related pathways were used to reveal the characteristics and nature of the differential metabolism of the wind cold and depressed lung syndrome in children. Results: 1. the results of the pattern recognition analysis showed that the wind cold and the lung syndrome can distinguish well between the healthy children and the healthy children, and many organic acids, amino acids, lipids and other metabolites and metabolic pathways were determined. Compared with healthy children, The serum alanine, aspartic acid, glutamic acid, glycine, serine, threonine, taurine, lysine and other organic acids are up regulated in the serum of children with wind cold and depressed lung syndrome, and the amino acid up-regulation of amino acids, such as aminobutyric acid, glycolic acid, glycerol, 1- palmitate monoglyceride, cholesterol, glucose and other.2. urine metabolomics pattern recognition analysis results show that wind cold and depressed lung syndrome and Although there is a certain separation trend among the healthy children, there are still overlapping overlapping, further modeling OPLS-DA, the two groups are completely separated, indicating that there are differences in metabolites. In urine metabolism, glycine, serine, tryptophan, beta hydroxybutyric acid, gluconic acid, D- galactose, inosine, uridine and so on are up-regulated, and hydroxyacetic acid, stearic acid, palmitic acid and so on are down regulated. The 1.GC-MS metabonomics technology platform can distinguish and preliminarily solve the differential metabolism between WC and normal healthy children (NH). The serum and urine metabolism of WC syndrome in children with.2. virus pneumonia are mainly metabolic disorders such as alanine, glycine, bovine sulfonic acid metabolism, peanut four enoic acid, palmitic acid metabolism and other metabolic disorders. Mark.
【学位授予单位】：南京中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R272
本文编号：2139666
[Abstract]:Background: Children's community-acquired pneumonia (CAP) has gradually become the first cause of death in children under 5 years of age. The statistics of children who die of pneumonia every year around the world are about 2 million. This accounts for the 200%. virus infection of the total number of children in the world, which is an important feature of children's CAP different from adults. Respiratory Syncytia1 Virus (RSV) accounts for the first [1], other viruses such as Adenovirus (ADV), influenza virus (Inf1uenza virus, IFV), human partial lung virus (Human meta-pneumoniae) parainfluenza virus (Human meta-pneumoniae), etc. As an important symptom of viral pneumonia at the beginning of children, how to comprehensively and scientifically explain the connotation and essence of the TCM syndrome has become an urgent problem to be solved in modern Chinese medicine. According to the corresponding research, the treatment of viral pneumonia in children is lack of complete effective, safe and ideal combination drug, and Ribavirin is the only one. AAP, which is carefully recommended by the American paediatrics Association, "may be able to use" synthetic nucleoside antiviral drugs. Compared with this, traditional Chinese medicine has shown obvious advantages in the treatment of viral pneumonia in children, and has been confirmed by a large number of clinical and experimental studies. Metabolomics (Metabolomics) is an important component of system biology. A new subject, [2]. metabolomics, which is a new subject in the nature of endogenous metabolites, quantity, species, and overall changes of organisms. It can effectively avoid the previous proteomics or genomics by using one or several indicators, or the expression of one or several genes blocking the pathway to predict or infer physiological or pathological conditions. "Real world", at the same time, it can be timely, effectively and objectively and sensitively map the organism, protein, cell or tissue "biochemical phenotypes" in the body after disturbance, and replace the single detection by the whole measure. This fits the basic theory of traditional Chinese medicine, the concept of holism, the concept of constant motion, is a kind of "aerial vision" replacing a single "jungle search". On the basis of this macro understanding, this subject uses the metabonomics method, combined with the biochemical tests of children's life signs, blood, urine routine, liver and kidney function, and discusses the significance of metabolic difference caused by the WC of viral pneumonia and wind cold depression, and tries to explain the syndrome of the wind cold and depressed lung syndrome of children with viral pneumonia from an early age. Objective: To explore the endogenous differential metabolism characteristics of serum and urine in children with viral pneumonia, wind cold and depression, and to explain the essence of differential metabolic syndrome in children with viral pneumonia, wind cold and depressed lung syndrome. Methods: clinical experiment of children viral pneumonia in wind cold depression and lung syndrome: selection can be included in Chinese and Western medicine. The standard viral pneumonia belongs to 30 children with wind cold and lung syndrome type, which is set as the wind cold group (WC). At the same time, 30 cases of normal healthy children (NH) were set up at the physical examination. The serum and urine of two groups of children were collected for second days in the hospital, and the WC group was obtained by gas chromatography-mass spectrometry (Gas-Chromatography-MassSpectrometry, GC-MS) simultaneously. The difference of endogenous metabolites in the serum and urine of NH group, based on the database to establish the syndrome related metabolic clusters of children with viral pneumonia, wind cold and depression, was pretreated by the online analysis platform XCMS Online, the NIST database and the existing standard, and MetaboAnalyst to determine the differential metabolites and metabolic pathways. The related pathways were used to reveal the characteristics and nature of the differential metabolism of the wind cold and depressed lung syndrome in children. Results: 1. the results of the pattern recognition analysis showed that the wind cold and the lung syndrome can distinguish well between the healthy children and the healthy children, and many organic acids, amino acids, lipids and other metabolites and metabolic pathways were determined. Compared with healthy children, The serum alanine, aspartic acid, glutamic acid, glycine, serine, threonine, taurine, lysine and other organic acids are up regulated in the serum of children with wind cold and depressed lung syndrome, and the amino acid up-regulation of amino acids, such as aminobutyric acid, glycolic acid, glycerol, 1- palmitate monoglyceride, cholesterol, glucose and other.2. urine metabolomics pattern recognition analysis results show that wind cold and depressed lung syndrome and Although there is a certain separation trend among the healthy children, there are still overlapping overlapping, further modeling OPLS-DA, the two groups are completely separated, indicating that there are differences in metabolites. In urine metabolism, glycine, serine, tryptophan, beta hydroxybutyric acid, gluconic acid, D- galactose, inosine, uridine and so on are up-regulated, and hydroxyacetic acid, stearic acid, palmitic acid and so on are down regulated. The 1.GC-MS metabonomics technology platform can distinguish and preliminarily solve the differential metabolism between WC and normal healthy children (NH). The serum and urine metabolism of WC syndrome in children with.2. virus pneumonia are mainly metabolic disorders such as alanine, glycine, bovine sulfonic acid metabolism, peanut four enoic acid, palmitic acid metabolism and other metabolic disorders. Mark.
【学位授予单位】：南京中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R272
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